Fluorinated androstanes



rates 3,045,032 FLUQRHNATED ANDRBSTANE Cecil H. Robinson, Qedar Grove, and Eugene P. Oliveto, Glen Ridge, N..l'., assignors to Schering Corporation, Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed Feb. 8, 1960, Ser. No. 7,116 6 Claims. '(Cl. 26tl--397.4)

Our novel l6,l difluoroandrostaneshave the following general formula:

Y z on i F wherein Z is a member of the group consisting of O, (H, 50R), (Ct-IOWBI' alkyl, 30R) and (oc-10W61 alkynyl, fiOR) wherein R andR are members of the group consisting of H and an acyl radical of a hydrocarbon carboxylic acid containing up to eight carbon atoms. R and R may be alike or different.

Our invention therefore includes novel compounds such as 16,16-difluroandrostane-3m-ol-l7-one (16,16-diiluoroandrosterone) 16,16-difluoroandrostane-3a,17,6-diol 16, 16 difluoroandrostanediol 30;,175), l6,16 difiuoro- 17cc methylandrostane 304,176 diol, 16,1-6 difluoro- 17a-ethinylandrostane-3u,17,8-diol, and the lower alkanoate esters thereof.

By lower alkyl is contemplated hydrocarbon radicals having up .to four carbon atoms and includes methyl, ethyl, n-propyl, isopropyl, n-butyl and the like.

By lower alkynyl is contemplated hydrocarbon radicals having up to four carbon atoms possessing a triple-bond stemming from the carbon attached to the l7-carbon of the steroid nucleus. Included in this groupv are radicals such as ethinyl, l-propynyl and l-butynyl.

The acyl radicals of hydrocarbon carboxylic acids containing up to eight carbon atoms are preferably radicals of lower alkanoic acids such as acetic, propionic, valer-ic, butyric, caproic acid and the like.

The novel 16,16-difluoroandrostanes of the general formula are therapeutically valuable in that they cause a reduction in serum cholesterol. This property renders our novel compounds valuable in the treatment and prevention of diseases which are accompanied by an increase in serum cholesterol, particularly, for example, in the treatment of atherosclerosis.

The preferred species of the therapeutically active 16,- 16-difluoroandrostanes of the general formula as described herein above is 16,16-difluoroandrostane-3a-ol-l7-one, which is useful as an intermediate for preparing the other 16,16-difluoro compounds of this invention as well as being therapeutically active per se.

Our novel compounds are conveniently prepared from androsterone (androstane-3a-ol-17-one) by utilizing the novel process described in the copending application of Robinson, Serial No. 7,107, filed February 8, 1960. According to this process, androsterone is converted to the intermediary 16-hydroxymethylene (l6-formyl) or 16- ethoxalyl androsterone by methods well known in the art; We prefer to formylate'the activated C-16 position by reacting androsterone with ethyl formate and sodium methoxide or sodium hydride utilizing as solvent, benzene or tetrahydrofuran or mixtures thereof. The l6-formyl derivative thereby obtained apparently exists in two tautomeric forms, namely formyl and hydroxymethylene. Alternatively, the l6-ethoxalyl derivative of androsterone is prepared according to procedures similar to those for preparing the 16-hydroxymethylene derivatives. by using ethyl oxalate as reagent instead of ethyl formate.

By reacting the intermediary l6-hydroxymethyleneandrosterone or l6-ethoxalylandrosteronewith perchloryl fluoride in the presence of alkoxide preferably potassium t-butoxide in t-butanol solvent, there is obtained 16,16-

difluoroandrosterone, a novel compound of our invention.

The compound 16,16-difluoroandrosterone, prepared as described above, may be transformed to the 17a-1ower alkynyl-l7fl-hydroxy or 17u-lOW6I' alkyl-l7/3-hydroxy analogs by known methods. androsterone is readily transformed to l6,l6-difiuoro l7a-methylandrostane-3a,17fi-diol by the well known Grignard reaction utilizing methyl magnesium iodide, .or to the corresponding l7ot-ethinyl derivative by means of sodium or potassium acetylide. The l7-hyclroxy compound, i.e. l6,16=difiuoroandrostane-3a,17,8-diol is conveniently obtained from the l7-keto analog by reduction with lithium aluminum hydride, sodium borohydride, platinum and hydrogen, and the like.

By substituting suitable reagents in the aforementioned reactions, such as ethyl magnesium bromide instead of methyl magnesium iodide in the Grignard reaction on 16,16-difluoroandrosterone, there are obtained higher alkyl homologs at C-17 for example, 16,16-difluoro-17aethylandrosterone-l7,8-01. homologs of 16,l6-difluoro-17a-ethinylandrosterone-17p- 01, it is preferred to alkylate the active hydrogen on the ethinyl moiety by means of lithium and methyl iodide, for example, to obtain 16,l6-difluoro-17a-(1-propynyl)-androstane-3a,l7/S-diol. When ethyl iodide and lithium are reacted with the aforementioned l7a-ethinyl derivatives 2 there is obtained the corresponding l7ot-butynyl compound, i.e. 16,16-d1'fiuor0-17a-(l'-butynyl)-androstanetone-3 fl-oll 7-one and perchloryl fluoride upon hydrogena-,

tion in ethyl acetate utilizing platinum oxide as catalyst yields l6,l6-difluoroandrostane-3B-ol-17-one. Conversion of, the 3 8-hydroXyl group to the 3-keto is effected by a chromic acid oxidation to give 16,16-difluoroandrostane- 3,17-dione. Alternatively, esterification of the iii-hydroxyl group with p-toluenesulfonic acid in pyridine, for eX- ample, gives 16,16-difiuoroandrostane-3,8-ol-l7-one-3 tosylate. Displacement of the 3B-tosylate by sodium acetate using known techniques to give thecorresponding 3a-ace- I toxy-16,l6-difiuoroandrostane-17-one followed by hydrolysis with ethanolic potassium hydroxide yields 16,16-

difluoroandrostane-Stat-01 17-one of our invention. In like manner, utilizing similar techniques other 16,16-difluoro S-androstenes described in copending application, Serial No. 7,107, filed February 8, 1960, such as 16,16-difluor'ol7a-methyl-5-androstene-3/8,17,8-diol are convertible to the a in corresponding 16,16-difluoroandrostanes of this invention,

3,945,032 I Patented July 17, 1 9 62 For example, 16,16-difluoro- I In preparing higher C-l7 The 3a-hydroxy-16,16-difluoroandrostanes of the general formula possessing an ester group at 17, are conveniently prepared by known techniques from the corresponding 17-hydroxy-l6,16-difluoroandrostane by selective esterification at C-17 with pyridine and a lower alkanoyl anhydride. For example, 16,16-difluoroandrostane-3a, 17B-diol reacted with approximately a molar equivalent of acetic anhydride in pyridine yields the 17-monoacetate, i.e. 16,l6-difluoroandrostane-3a,17/3-diol 17-acetate. By substituting other lower alkanoyl anhydrides such as propionyl anhydride or caproic anhydride, the corresponding 17-lower alkanoate is obtained, i.e. the 17-propionate and 17-caproate respectively of l6,16-difluoroandrostane-3u, 17/i-diol.

When preparing 3,17-diesters of the general formula, the corresponding 3,17-diol is preferably reacted in pyridine with at least two moles of acid anhydride per mole of steroid. Usually an excess of acid anhydride is used, and it is often desirable to apply heat to hasten the esterification process.

The following examples are shown by way of illustration only and are not to be construed as limiting the scope of our invention, the scope of our invention being defined by the appended claims.

EXAMPLE 1 1 6,1 6-Difluoroandrostane-3 a-Ol-I 7-0ne A. 16-hydr0xymethyIeneandr0stane-3a-0l-17-0ne.To a solution of one gram of androsterone in 20 ml. of tetrahydrofuran is added one gram of sodium methoxide. While the reaction is stirred under an atmosphere of nitrogen, 8 ml. of ethyl formate is added dropwise over a 30 minute period. The reaction mixture is then stirred under nitrogen 18 hours at room temperature. Ice and water (150 ml.) is added to give a yellow solution which is stirred and neutralized by the dropwise addition of concented hydrochloric acid. A solid precipitates which is filtered, washed with water and dried in vacuo to give 1fi-hydroxymethyleneandrostane-3a-ol-17-one,

AL??? 265 mp (e 9,100)

lized from hexane-ether to give 16,16-difiuoroandrostane- 3e-oll7-one, M.P. l33-l36 G, [:1 +102".

EXAMPLE 2 A. 6.5 ml. portion of a 17% suspension of sodium acetylide in xylene is centrifuged and the supernatant liquid removed and replaced by ml. of dimethylsulfoxide. The resultant suspension is added to a stirred solution of one gram of 16,16-difiuoroandrostane-3a-ol-17-one in 100 ml. of dirnethylsulfoxide at room temperature. The reaction mixture is stirred at room temperature for minutes, then water and ice are added. A solid separates which is filtered, washed with water, dried and crystallized from acetone-hexane to give 16,16-difluoro-17ucthinylandrostane-l3a-17B-diol.

In a similar manner, by substituting sodium methyl acetylidefor sodium acetylide in the above procedure, there is obtained 16,16 ditluoro-17a-(1-propynyl)-androstane-3a-l7B-diol.

lit

4 EXAMPLE 3 To a stirred solution of methyl magnesium iodide (prepared from 3 g. of magnesium and 7.5 ml. of methyl iodide) in 250 ml. of anhydrous ether is added dropwise with stirring one gram of 16,16-difluoroandrostane- 3e-ol-17-one (the compound of Example 1) in 50 ml. of tetrahydrofuran. 150 ml. more of tetrahydrofuran is added and the mixture is distilled until 250 ml. of distillate is collected. The reaction mixture is refluxed for one hour longer, then cooled and diluted with ice-cold 10% aqueous aluminum sulfate solution. A solid separates which is filtered, washed with water, dried and chromatographed on Florisil. Hexane-ether (1:1) eluates are combined and evaporated in vacuo to give 16,16'diflllOr0-17u-I1'16thylandrostane-3a,17;9-diol.

In a similar manner, by substituting other alkyl Grignard reagents such as ethyl magnesium iodide and n-propyl magnesium bromide for methyl magnesium iodide in the above procedure, there is obtained 16,16-difluoro-17aethylandrOstane-Ba,17,8-diol and 16,16-difluoro-17a-n-propylaridrostane-3a,17,6-dio1, respectively.

EXAMPLE 4 16,16-Diflu0r0androstane-3u,17,8-Di0l 500 mg. of 16,16-difluoroandrostane-3a-ol-17-one (the compound of Example 1) is dissolved in 50 ml. of isopropanol to which is added 900 mg. of sodium borohydride. The solution is heated on the steam bath for one hour, then cooled and diluted With 150 ml. of water. A solid precipitates which is filtered, washed with water, dried and crystallized from aqueous methanol to give 16. 16-difiuoroandrostane-3u,17,8-diol.

EXAMPLE 5 1 6,1 6 -Di fluoraandrostan 2-3 a,1 7f3-Di0l 1 7 -Acetate To 3.28 g. of 16,16-difiuoroandrostane-3a-17fi-diol (the compound of Example 4) in 24 ml. of pyridine is added 1.03 ml. of acetic anhydride. The solution is left at room temperature for eight hours, then diluted with water. A solid separates which is filtered, washed with Water and dried to give 16,16-difluoroandrostane-3a,17;3-diol 17-acetate.

By substituting other lower alkanoic acid anhydrides such as propionic or caproic for acetic anhydride in the above procedure there is obtained the corresponding 17- propionate or 17-caproate respectively of 16,16-difluoroandrostane-3a,17/3-diol.

EXAMPLE 6 Alternate Method 0 Preparing 16,16-Difluor0androstane- 3124-01-1 7-One A. 16-ethoxalylandrostaneda-ol-Z7-one.--To a stirred solution of 10 g. of sodium methoxide in 60 ml. of ethyl oxalate and 60 ml. of benzene under an atmosphere of nitrogen there is added dropwise a solution containing 10 g. of androstane-3u-ol-17-one in 5 m1. of benzene and m1. of tetrahydrofuran. The reaction mixture is stirred under nitrogen at room temperature for 18 hours. The mixture is then filtered, poured into 350 ml. of water with stirring and neutralized with 6 N hydrochloric acid.

' A solid separates which is filtered, washed with water and dried to give 16-ethoxalylandrostane-3a-ol-17-one which is used without further purification in the following procedure.

B. 16,16-difluoroandrostane-u-ol-l7-one.-16-ethoxalylandrostane-3u-ol-17-one is reacted with perchloryl fluoride in t-butanol in the presence of potassium t-butoxide in the manner described in Example 113. The resultant product is isolated and purified as described to give 16, 16-difluoroandrostauc-3a-ol-l7-one.

5 EXAMPLE 7 1 6,16-Difluoroandrstane-3a-Ol-17-One 3-A cetate To 3.28 g. of 16,16-diiluoroandrostane-3et-ol-17-one (the compound of Example 1) in 24 ml. of pyridine is 5 added 1.03 ml. of acetic anhydride. The solution is heated on a steam bath for one hour then diluted with water. A solid separates which is filtered, washed with water, dried and recrystallized from acetone-hexane to give 16,16-difluoroandrostane-3a-ol-17-one 3-acetate.

In a similar manner, by substituting other lower alkanoic acid 'anhydrides such as propionic or valeric for acetic anhydride in the above procedure there is obtained the corresponding 3-propionate and 3-valerate, respectively of 16,16-difluoroandrostane-3 oc-Ol-17-0116.

EXAMPLE 8 l6,16-Difluoroandr0stane-3a,17fi-Di0l Diacetate To 3.28 g. of 16,16-Cliflll0103l1dIOSt3Il6-3oc,l7l3-di0l (the compound of Example 4) in 50 ml. of pyridine is added 2.5 ml. of acetic anhydride. The solution is heated on the steam bath for one hour .then diluted with water. A solid separates which is filtered, Washed with Water, dried and recrystallized from acetone-hexane to give 16,

l6-difiuoroandrostane-3a,17,8-diol diacetate. 25

In a similar manner, by substituting other lower alkanoic acid anhydrides such as propionic or Valerie for acetic anhydride in the above procedure there is obtained the corresponding 3,17-dipropionate and 3,17-divalerate respectively of 16,16-difluoroandrostane-3u,17p-diol.

wherein Z is a member of the group consisting of O,

loweralkynyl and H loweralkyl wherein R and R are members of the group consisting of H and an acyl radical of a hydrocarbon carboxylic acid containing up to eight carbon atoms.

. 16,16-difiuoroandrostane-3u-ol-17-one.

. 16,16-difluoroandrostane-3a,17p-diol.

. 16,16-difluoro-l7a-methylandrostane-3u,17/3-di0l. '16,16-difluoro-17u-ethinylandrostane-3a,17fl-diol. 16,l6-diflnoroandrostane-3u-ol-17-one 3-acetate.

gmuttsono References Cited in the file of this patent Pappo et al.l' Journal of the American Chemical Society, vol. 78 (1956). Pages 6347-6353 relied on. 

1. A COMPOUND HAVING THE FOLLOWING GENERAL FORMULA: 